Method for effective de-oxygenation of product containers for use as containers for oxygen sensitive products

ABSTRACT

The invention generally relates to the use of liquid nitrogen to displace air, or other water and/or oxygen containing atmospheres, from containers prior to filling with a highly sensitive product. The process in general has two steps: a) depositing a volume of liquid nitrogen into the cavity of an empty container and b) applying a vacuum to the cavity of the container. The vacuum will accelerate vaporization and thereby shorten the liquid nitrogen vaporization time frame. This procedure results in a highly effective one step de-oxygenation and/or de-humidification of the container cavity. Further, the evacuation ensures complete liquid nitrogen vaporization prior to product filling.

TECHNICAL FIELD

The present disclosure relates to methods of packaging oxygen sensitive products in containers pre-filled with an inert atmosphere.

BACKGROUND ART

Liquid nitrogen is known for use in pressurizing containers in the beverage industry and other consumer products. U.S. Pat. No. 6,182,715 describes an apparatus and method for pressurizing containers using liquid nitrogen. These pressurization techniques are not related to nor do they accomplish meaningful levels of de-oxygenation of containers.

Removal of oxygen and/or moisture from the interior of a container prior to filling with a product can be critical to the stability and shelf life of products. Highly oxygen and/or water sensitive products should be placed into containers that are substantially free of oxygen and/or water.

Previous applications of liquid nitrogen as a container de-oxygenation agent are exemplified by U.S. Pat. No. 6,105,341 to Campbell. As discussed by Campbell, “[t]he conventional liquid nitrogen injection process suffers from many problems. One problem is that it is difficult to properly time the process so that at the exact time when the lid is seamed to the container body, (1) substantially all of the air has been displaced so that the sealed container has less than about 2% oxygen, (2) all of the liquid nitrogen has vaporized, and (3) no surrounding air has flowed back into the container body.” The Campbell process is defined by claim 1 of the Campbell patent as the sequential steps of:

(a) filling a succession of container bodies with goods; (b) injecting the succession of container bodies with a predetermined amount of liquid nitrogen; (c) covering the open tops of the container bodies with lids; and (d) applying a biasing force against the lids to maintain the lids on the liquid nitrogen filled container bodies until the container bodies reach the seaming mechanism, the biasing force being sufficient to allow (i) a portion of nitrogen gas from vaporization of the liquid nitrogen, and (ii) air originally present in the container body, to escape from the container body, while preventing surrounding air from entering the container body.

This approach has deficiencies that are particularly relevant to Highly oxygen and/or water sensitive products. First, liquid nitrogen injection occurs after product filling. As can be seen in Campbell FIG. 6, Air (i.e. oxygen and moisture) is trapped in the container and purged over time by the expansion of the co-enclosed liquid nitrogen. As a consequence, the product is exposed to air during the packaging process. The final container atmosphere will also retain some amount of the original air. This process may yield a final atmosphere of less than 2% oxygen which is suitable for some foodstuffs. However, highly oxygen and/or water sensitive products will not be shelf stable under such conditions. In addition, the Campbell process exposes the product to direct contact with liquid nitrogen. Many pharmaceuticals and other products cannot tolerate direct liquid nitrogen exposure. The liquid nitrogen intolerant products will be destroyed or otherwise rendered unsuitable for human or animal use if exposed to liquid nitrogen.

For highly sensitive products, industrial practices packaging processes have been developed to cope with oxygen sensitivity pharmaceuticals in particular.

The product to be contained is normally pyrogenated (sterilized) and deoxygenated using nitrogen sparging. The container in which the product is to be filled is autoclaved and dried.

PRIOR ART EXAMPLE 1

The container is purged with gaseous nitrogen. Because nitrogen has the similar properties as air (density in particular), a large quantity of nitrogen is required to displace air to the necessary oxygen levels. Finally product loading into the container is performed as quickly as possible. A common sequence in the art is:

-   -   1) Gaseous nitrogen purge     -   2) Pull vacuum to remove nitrogen     -   3) Another gaseous nitrogen purge     -   4) Fill product     -   5) One more gaseous nitrogen purge     -   6) Seal the container

PRIOR ART EXAMPLE 2

-   -   1) The first step involves pulling a vacuum of 200 millibar         (absolute) to evacuate air from the container.     -   2) This step is rapidly followed by a container backfilling with         argon. Because argon is heavier than air, argon stays in the         vial prior to filling with drug in the next step.     -   3) Product is then filled into the containers, displacing argon         from the container. Immediately after filling, the container is         flushed with nitrogen.     -   4) Now the vials come to the final stage where:         -   a) Vacuum is pulled in the container headspace         -   b) A nitrogen flush         -   c) Another vacuum pull         -   d) Another nitrogen flush         -   e) The container is sealed

As illustrated by the above, the prior art processes for packaging highly sensitive products suffer from a number of undesirable features including:

-   -   Use of argon for very low oxygen content in the product         container. Argon is a relatively expensive gas compared to         nitrogen.     -   Use of several gaseous nitrogen purges to sufficiently reduce         the oxygen content in the container.

The present invention in comparison:

-   -   Avoids use of expensive argon gas     -   Significantly reduces the amount of nitrogen gas used and thus         the cost of nitrogen gas     -   Significantly simplifies the de-oxygenation/de-humidification         process to, in some instances, a two step process that achieves         the necessary degree of de-oxygenation/de-humidification for         highly sensitive products     -   Product is not directly contacted by liquid nitrogen.

BRIEF SUMMARY OF THE INVENTION

The invention is described in part by the following numbered sentences:

1. A process for the removal of an atmosphere within a container cavity comprising the steps of:

-   -   a) dispensing a volume of liquid nitrogen into the container         cavity prior to any step of a product addition,     -   b) permitting the liquid nitrogen to vaporize completely, and     -   c) filling a product into the container cavity.         2. The process of sentence 1, further comprising applying a         sufficient vacuum to the container cavity having the volume of         liquid nitrogen to thereby accelerate the vaporization of the         liquid nitrogen.         3. The process of sentence 1, wherein step c) is filling the         container with a highly sensitive product and further comprising         step d) sealing the container closed to produce a packaged         highly sensitive product.         4. The process of sentence 3 wherein the product is a highly         oxygen sensitive product.         5. The process of sentence 3 or 4 wherein the product is a         highly water sensitive product.         6. The process of any one of the preceding numbered sentences         wherein the product is a liquid nitrogen intolerant product.         7. The process of any one of the preceding numbered sentences         wherein the container is sterilized prior to step a).         8. The process of any one of the preceding numbered sentences         wherein volume of liquid nitrogen is the amount capable of         producing a volume of vaporized nitrogen gas that is at least         equal to the volume of the container cavity.         9. The process of sentence 8 wherein the volume of vaporized         nitrogen gas is at least 5% greater than the volume of the         container cavity.         10. The process of any one of the preceding numbered sentences         wherein step a) is repeated at least once.         11. The process of any one of the preceding numbered sentences         wherein steps a) and b) are repeated at least once.         12. The process of sentence 3 and sentences 4, 5 and 7-11 as         they depend on sentence 3, further comprising step d) adding an         additional volume of liquid nitrogen to the container cavity         with the highly sensitive product to flush out a headspace of         the container cavity above the highly sensitive product, with         the proviso that the product is not a liquid nitrogen intolerant         product.         13. The process of sentence 3 and sentences 4-12 as they depend         on sentence 3, wherein a final enclosed atmosphere with the         container comprises less than 1.5% oxygen and/or less than 40%         relative humidity.         14. The process of sentence 13 wherein a final enclosed         atmosphere with the container comprises less than 1% oxygen         and/or less than 20% relative humidity.         15. A packaged product produced by the process of sentence 3 and         sentences 4-14 as they depend on sentence 3.         16. A product packaging apparatus comprising:     -   a) a product container conveyance line,     -   b) a liquid nitrogen dispensing device configured to add a         measured amount of liquid nitrogen into an empty product         container cavity,     -   c) a product filling station configured to draw a measured         amount of a product from a product stock supply and fill the         product container cavity with the product, and     -   d) a product container sealing device to seal the product         container closed,     -   wherein the measured amount of liquid nitrogen is sufficient to         completely displace a pre-existing container cavity atmosphere         when the liquid nitrogen completely vaporizes, and     -   wherein the liquid nitrogen dispensing device and the product         filling station are spatially arranged along the product         container conveyance line to ensure the measured amount of         liquid nitrogen will fully vaporize prior to product filling         during operation of the apparatus.         17. The apparatus of sentence 16 wherein the volume of vaporized         nitrogen gas is at least 5% greater than the volume of the         container cavity.         18. The apparatus of sentence 16, further comprising a liquid         nitrogen dispensing device configured to add a measured amount         of liquid nitrogen into a filled product container cavity with         an amount of liquid nitrogen that is sufficient to flush out a         headspace of the filled product container cavity, with the         proviso that the product is not a liquid nitrogen intolerant         product.         19. A product packaging apparatus comprising:     -   a) Means for conveying a product container,     -   b) Means for dispensing a measured amount of liquid nitrogen         into an empty product container cavity,     -   c) Means for filling the empty product container cavity with a         product, and     -   d) Means for sealing the product container closed, characterized         in that the measured amount of liquid nitrogen is sufficient to         completely displace a pre-existing container cavity atmosphere         when the liquid nitrogen completely vaporizes.

DISCLOSURE OF INVENTION

“Highly sensitive products” are defined as products that suffer from a shortened shelf life (e.g. chemical stability) or are physically changed (e.g. hygroscopic moisture absorption by a powder) to render the product unsuitable for human or animal use when exposed to the atmosphere as compared to when the products are maintained in a substantially pure (e.g. 99.9%) inert gas atmosphere of nitrogen.

“Highly oxygen sensitive products” are defined as products with a shortened shelf life if exposed to greater than 1.5% oxygen. Some highly oxygen sensitive products require 1% or less oxygen for stability.

“Highly water sensitive products” are defined as products that react with moisture to change in chemical makeup or physical properties, thereby rendering the product unsuitable for human or animal use. An example is a highly hygroscopic powder agglomerating due to moisture absorption. Highly water sensitive products should be stored in atmospheres having as little moisture as possible such as a relative humidity of 40% or less, 20% or less or even 10% or less, depending on the specific moisture uptake rate and anticipated product storage period.

“Liquid nitrogen intolerant products” are defined as products that are altered in chemical makeup or physical properties by direct contact with liquid nitrogen. In some cases this alteration renders the product unsuitable for human or animal consumption and/or reduces the effectiveness of the product for the product's intended use. For example, a liquid nitrogen intolerant antibiotic may be reduced in potency by exposure to liquid nitrogen rendering the normal dose of antibiotic insufficient to treat an indicated infection.

The invention generally relates to the use of liquid nitrogen to displace air, or other water and/or oxygen containing atmospheres, from containers prior to filling with a highly sensitive product. The process in general has two steps: a) depositing a volume of liquid nitrogen into the cavity of an empty container and b) applying a vacuum to the cavity of the container. The vacuum will accelerate vaporization and thereby shorten the liquid nitrogen vaporization time frame. This procedure results in a highly effective one step de-oxygenation and/or de-humidification of the container cavity. Further, the evacuation ensures complete liquid nitrogen vaporization prior to product filling.

In general, the container will be sterilized (autoclave and dried, gamma irradiated, etc.). Liquid nitrogen expands approximately 700 times upon vaporization. Thus a small volume of liquid nitrogen placed at the bottom of a container cavity will expand into a gas and push out the pre-existing container atmosphere. A liquid nitrogen dispensing apparatus will generally be positioned in close proximity to the product filling point, the closer the better. The container having the liquid nitrogen is generally exposed to a vacuum sufficient to accelerate the liquid nitrogen's vaporization. Accelerating the liquid nitrogen vaporization increases the efficiency of the removal of the pre-existing atmosphere. The evacuation and liquid nitrogen deposition steps may be concurrent or in either order (deposition-evacuation or evacuation-deposition) as long as the liquid nitrogen experiences the vacuum sufficiently to shorten the time required for complete liquid nitrogen vaporization. Optionally, additional volumes of liquid nitrogen may be deposited into the cavity of the container either while the container is being evacuated or by alternating between separate liquid nitrogen deposition and evacuation steps. Product may then be dispensed into the container, generally under controlled atmosphere conditions such as a nitrogen atmosphere as is known and practiced in the art. After product filling, an additional volume of liquid nitrogen may optionally be added prior to sealing closed the container to a) flush out the headspace above the product and/or b) pressurize the container.

Guidance on Certain Operating Parameters

In general the ratio of the Volume of the Container/Volume of Liquid Nitrogen will be 730 or more. For example, 3 to 4 ml of Liquid Nitrogen may be used to completely evacuate a 5″ diameter×9″ tall container. The volume of liquid nitrogen is in part dependent on the distance between or time between liquid nitrogen addition and evacuation. More Liquide nitrogen may be added to compensate for extended travel times to the evacuation position to ensure sufficient liquid nitrogen is present for the evacuation step.

The speed of the container movement on a production line will dictate the location of the liquid nitrogen addition on the production line to ensure total vaporization of the liquid nitrogen prior to product filling but minimize the time between full vaporization and product filling. The evacuation step ensures complete vaporization and allows one to shorten the time for evaporation. The shorter the time/distance between evacuation and product filling, the better.

Product oxygen content is important as product derived oxygen affects the final oxygen content in the container. Hence recommend that the product is sparged properly with Nitrogen prior to filling in the container.

The travel between a container filling station and the sealing station should be as short as possible. For long travel the production line should be enclosed with a nitrogen blanket, e.g., under a hood providing a positive pressure of Nitrogen gas.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a representative product dispensing scheme falling within the scope of the invention.

MODE(S) FOR CARRYING OUT THE INVENTION

FIG. 1 shows a schematic of an exemplary production line for filling a product into a container. Empty containers 10 are transported by conveyor system 20 into product filling station 30. Product is dispensed from bulk product source 40. Seamer 50 closes and seals the filled containers 60 which then exit the conveyor system 70. Prior to filling station 30, liquid nitrogen dispenser 80 deposits a pre-determined volume of liquid nitrogen into the container 10. The pre-determined volume is the amount necessary to produce a volume of vaporized nitrogen gas at least equal to the volume of the container cavity. Generally the pre-determine volume will be in excess of this minimum amount by at least 5%. The conveyor system 20 then moves the container to the evacuation station 90. A vacuum sufficient to accelerate the vaporization of the liquid nitrogen is applied to the container cavity. The container is then moved to filling station 30 for filling with product. Between the filling station 30 and the seamer 50 are optional production line components hood 100 and second liquid nitrogen dispenser 110. The hood 100 maintains the filled containers in a controlled atmosphere (e.g. Nitrogen) and is generally used if the distance to the seamer 50 is far enough to result in some oxygen contamination in the containers 10 during transit. Second liquid nitrogen dispenser 110 deposit a volume of liquid nitrogen sufficient to flush out the headspace above the product in the container cavity prior to closure and sealing by the seamer 50. This second liquid nitrogen dispenser is generally not used in cases where a hood 100 is in place or where the distance to the seamer 50 is sort.

INDUSTRIAL APPLICABILITY

The process described herein is suitable for use in the manufacture and packaging of oxygen sensitive products such as certain pharmaceuticals. 

1. A process for the removal of an atmosphere within a container cavity comprising the steps of: a) dispensing a volume of liquid nitrogen into the container cavity prior to any step of a product addition, b) permitting the liquid nitrogen to vaporize completely, and c) filling a product into the container cavity.
 2. The process of claim 1, further comprising applying a sufficient vacuum to the container cavity having the volume of liquid nitrogen to thereby accelerate the vaporization of the liquid nitrogen.
 3. The process of claim 1, wherein step c) is filling the container with a highly sensitive product and further comprising step d) sealing the container closed to produce a packaged highly sensitive product.
 4. The process of claim 3 wherein the product is a highly oxygen sensitive product.
 5. The process of claim 3 wherein the product is a highly water sensitive product.
 6. The process of any claim 1 wherein the product is a liquid nitrogen intolerant product.
 7. The process of claim 1 wherein the container is sterilized prior to step a).
 8. The process of claim 1 wherein volume of liquid nitrogen is the amount capable of producing a volume of vaporized nitrogen gas that is at least equal to the volume of the container cavity.
 9. The process of claim 8 wherein the volume of vaporized nitrogen gas is at least 5% greater than the volume of the container cavity.
 10. The process of claim 1 wherein step a) is repeated at least once.
 11. The process of claim 1 wherein steps a) and b) are repeated at least once.
 12. The process of claim 3, further comprising step d) adding an additional volume of liquid nitrogen to the container cavity with the highly sensitive product to flush out a headspace of the container cavity above the highly sensitive product, with the proviso that the product is not a liquid nitrogen intolerant product.
 13. The process of claim 3, wherein a final enclosed atmosphere with the container comprises less than 1.5% oxygen and/or less than 40% relative humidity.
 14. The process of claim 13 wherein a final enclosed atmosphere with the container comprises less than 1% oxygen and/or less than 20% relative humidity.
 15. A packaged product produced by the process of claim 3 and having a final enclosed atmosphere with the container comprises less than 1.5% oxygen and/or less than 40% relative humidity.
 16. A product packaging apparatus comprising: a) a product container conveyance line, b) a liquid nitrogen dispensing device configured to add a measured amount of liquid nitrogen into an empty product container cavity, c) a product filling station configured to draw a measured amount of a product from a product stock supply and fill the product container cavity with the product, and d) a product container sealing device to seal the product container closed, wherein the measured amount of liquid nitrogen is sufficient to completely displace a pre-existing container cavity atmosphere when the liquid nitrogen completely vaporizes, and wherein the liquid nitrogen dispensing device and the product filling station are spatially arranged along the product container conveyance line to ensure the measured amount of liquid nitrogen will fully vaporize prior to product filling during operation of the apparatus.
 17. The apparatus of claim 16 wherein the volume of vaporized nitrogen gas is at least 5% greater than the volume of the container cavity.
 18. The apparatus of claim 16, further comprising a liquid nitrogen dispensing device configured to add a measured amount of liquid nitrogen into a filled product container cavity with an amount of liquid nitrogen that is sufficient to flush out a headspace of the filled product container cavity, with the proviso that the product is not a liquid nitrogen intolerant product. 